Variant X-69161797-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001032396.4(PJA1):c.1277A>G(p.His426Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,098,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000010 ( 0 hom. 3 hem. )

Consequence

PJA1
NM_001032396.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

Variant links:

Genes affected

PJA1 (HGNC:16648): (praja ring finger ubiquitin ligase 1) This gene encodes an enzyme that has E2-dependent E3 ubiquitin-protein ligase activity. This enzyme belongs to a class of ubiquitin ligases that include a RING finger motif, and it can interact with the E2 ubiquitin-conjugating enzyme UbcH5B. This gene is located in an area of chromosome X where several X-linked cognitive disability disorders have been associated, and it has also been found as part of a contiguous gene deletion associated with craniofrontonasal syndrome, though a direct link to any disorder has yet to be demonstrated. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

PJA1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.122339964).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PJA1	NM_001032396.4 linkuse as main transcript	c.1277A>G	p.His426Arg	missense_variant	2/2	ENST00000374571.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PJA1	ENST00000374571.5 linkuse as main transcript	c.1277A>G	p.His426Arg	missense_variant	2/2	1	NM_001032396.4	P2	Q8NG27-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183478

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1098253

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

363607

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000950

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.1442A>G (p.H481R) alteration is located in exon 2 (coding exon 1) of the PJA1 gene. This alteration results from a A to G substitution at nucleotide position 1442, causing the histidine (H) at amino acid position 481 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-1.0

CADD

Benign

DANN

Benign

0.34

DEOGEN2

Benign

0.087

T;.;T;.

FATHMM_MKL

Benign

0.22

M_CAP

Benign

0.0047

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.039

D;T;D;D

Sift4G

Benign

0.064

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.062

MutPred

0.29

Gain of solvent accessibility (P = 0.039);.;Gain of solvent accessibility (P = 0.039);.;

MVP

0.26

MPC

0.39

ClinPred

0.022

GERP RS

-2.7

Varity_R

0.085

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over